Powder for oral suspension containing tadalafil

ABSTRACT

This document discloses a powder formulation of tadalafil for oral administration. Also disclosed are a method of preparing the powder formulation, a suspension dosage form of tadalafil and a method of treating diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/237,319, filed Apr. 22, 2021, which is a continuation-in-part ofInternational Application No. PCT/US21/26636, filed Apr. 9, 2021. Thecontents of the applications are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

This patent document discloses a novel formulation of tadalafil or itspharmaceutically acceptable salt, a method for its preparation and itsuse in medical therapy.

BACKGROUND

Tadalafil is marketed in the United States by Eli Lilly and Company,under the trade name Cialis and Adcirca. Cialis is for the indication oferectile dysfunction and Adcirca is for the indication of pulmonaryarterial hypertension (PAH), both are immediate release tablets. As aresult, hospital pharmacists are often required to compound liquidformulations using crushed tadalafil tablets for pediatric patients andpatients who cannot swallow tablets. A need exists for an improvedformulation of Tadalafil.

SUMMARY

The powder formulation described herein allows for convenient oraladministration of Tadalafil. The formulation resolved the doseinaccuracy issue due to the precipitation of crushed tadalafil tabletsin a suspension system. Further, the formulation substantially improvesthe stability and dose accuracy of the medication.

An aspect of this patent document provides a powder formulation suitablefor reconstitution with a pharmaceutically acceptable carrier to form astable suspension oral dosage form. The formulation contains tadalafilor a pharmaceutically acceptable salt thereof and a suspending agent.The suspending agent is effective for maintaining a sedimentation volumeratio of more than about 0.8 for at least 24 hours after the powderformulation is reconstituted into an aqueous suspension.

In some embodiments, less than about 0.5% of the tadalafil or thepharmaceutically acceptable salt thereof decomposes for about 3 monthsafter the powder formulation is reconstituted into the suspension.

In some embodiments, tadalafil or a pharmaceutically acceptable salt isin an amount of 1mg/ml to 50mg/ml after the powder formulation isreconstituted into the suspension. In some embodiments, the amount is5mg/ml.

In some embodiments, the suspending agent is in an amount of 0.5mg/ml to8mg/ml after the powder formulation is reconstituted into thesuspension. In some embodiments, the amount is 4 mg/ml.

In some embodiments, the tadalafil or the pharmaceutically acceptablesalt thereof and the suspending agent have a ratio ranging from about5:0.5 to about 5:8 by weight. In some embodiments, the ratio is about5:4 by weight.

In some embodiments, the suspending agent is selected from the groupconsisting of hydrocolloid gum, cellulosic derivative, a polysaccharide,alginate, acrylic acid copolymer, Polyvinylpyrrolidone,aluminiummagnesium silicate, and any combination thereof. In someembodiments, the suspending agent is hydrocolloid gum. In someembodiments, the suspending agent is xanthan gum.

In some embodiments, the sedimentation volume ratio remains more thanabout 0.8 within 24 hours after the powder formulation is reconstitutedinto the suspension. In some embodiments, the suspension is achievedwithin about 3 minutes after the powder formulation is reconstitutedwith water. In some embodiments, the suspension is homogeneous.

In some embodiments, the suspension provides an in vitro release of atleast about 75% of the tadalafil after 10 minutes (USP dissolutionapparatus 2, in 1000 ml of 0.5% SLS at 50 rpm). In some embodiments, thepowder formulation after being reconstituted into the suspensionprovides a release of the tadalafil bioequivalent to Adcirca tablet ofthe same dose. In some embodiments, the suspension prepared from thepowder formulation provides a release of the tadalafil bioequivalent toa non-suspension dosage form (e.g. Adcirca tablet), which provides atherapeutically effective blood concentration of tadalafil.

In some embodiments, the tadalafil or the pharmaceutically acceptablesalt thereof has a D90 ranging from about 1 μm to about 20 μm prior tobeing mixed with the suspending agent.

In some embodiments, the formulation further contains glidants includingfor example silicon dioxide, starch, talc and any combination thereof inabout 0% to about 10%. In some embodiments, the glidant is silicondioxide. In some embodiments, silicon dioxide amount is about 2.5%.

In some embodiments, the formulation further contains a diluent selectedfrom the group consisting of sucrose, dextrose, mannitol, sorbitol,maltitol, starch, lactose, microcrystalline cellulose, and anycombination thereof in about 10% to about 98% by weight of the powderformulation. In some embodiments, the diluent is sorbitol.

In some embodiments, the formulation further contains a buffering agentselected from the group consisting of sodium citrate, citric acid,fumaric acid, tartaric acid, potassium citrate, sodium bicarbonate,potassium bicarbonate, sodium dihydrogen phosphate, disodium hydrogenphosphate, sodium hydroxide and potassium dihydrogen phosphate.

In some embodiments, the formulation further contains a preservativeselected from the group consisting of Methyl Paraben or its sodium salt,Ethyl Paraben or its sodium salt, Propyl Paraben or its sodium salt,Sodium Benzoate, benzoic acid, Sorbic Acid, potassium sorbate, propionicacid and any combination thereof in about 0% to about 10%.

In some embodiments, the reconstituted suspension has a pH in the rangeof 2 to 6 after the powder formulation is reconstituted into thesuspension.

In some embodiments, the reconstituted suspension is easily pourable andhas a viscosity in the range of 10 to 5000 cP at 25° C.

Another aspect provides a method of preparing the powder formulationdisclosed herein. The method includes

-   -   (a) mixing tadalafil or a pharmaceutically acceptable salt        thereof with a first portion of glidant to obtain a first        mixture; and    -   (b) mixing the first mixture with one or more additional        excipients.

In some embodiments, the method further includes mixing the firstmixture with a first portion of diluent prior to step (b). In someembodiments, the method further includes mixing the first mixture,during step (b) or after step (b) with a second portion of the glidantand/or a second portion of diluent. In some embodiments, the glidant issilicon dioxide and the diluent is sorbitol.

Another aspect of the invention provides a suspension includingtadalafil or a pharmaceutically acceptable salt thereof or a derivativethereof and a suspending agent. The suspension maintains a sedimentationvolume ratio of more than about 0.8 for at least 24 hours after thesuspension is prepared. In some embodiments, the suspension can beprepared from the above described powder formulation by reconstitutionor by mixing the necessary components in suitable means as long as theresulting suspension achieves a desirable profile for oraladministration.

In some embodiments, the ratio between the tadalafil (or apharmaceutically acceptable salt thereof or a derivative thereof) andthe suspending agent in the suspension ranges from about 10:1 to about5:8 by weight. In some embodiments, the ratio is about 5:4 by weight. Insome embodiments, the suspending agent is hydrocolloid gum. In someembodiments, the suspending agent is xanthan gum.

In some embodiments, the ratio of area under curve (AUC 0-inf) betweentadalafil suspension to Adcirca tablet with the same dose is between 0.8to 1.25 after oral administration.

In some embodiments, the ratio of a maximum tadalafil plasmaconcentration (Cmax) between tadalafil suspension to Adcirca tablet withthe same dose is between 0.7 to 1.20 after oral administration.

In some embodiments, the plasma concentration profile at steady state ischaracterized by a maximum tadalafil plasma concentration to averageplasma concentration ratio (Cmax/Cave) of about 1.4 to 1.9 afteradministration.

In some embodiments, the plasma concentration profile at steady state isfurther characterized by a minimum tadalafil plasma concentration toaverage plasma concentration ratio (Cmin/Cave) of about 0. 5 to 0.8after administration.

Another aspect of the patent document provides a method of treating adisease comprising administering the suspension described herein to asubject in need, wherein the disease is selected from the groupconsisting of erectile dysfunction, enlarged prostate and pulmonaryarterial hypertension. Other exemplary applications include treatment ofHeart failure, hypertension, Left ventricle diastolic dysfunction,scleroderma spectrum of disease, Systemic Sclerosis, Raynaud's, fetalgrowth restriction, Mountain Sickness, Skeletal Muscle and PerceptualFatigue, Interstitial Lung Disease of Scleroderma, Chronic ObstructivePulmonary Disease, Duchenne Muscular Dystrophy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of xanthan gum percentage on dissolution of anexemplary formulation.

FIG. 2 shows the effect of sorbitol percentage on dissolution of anexemplary formulation.

FIG. 3 shows physical stability of suspension after reconstitution of anexemplary formulation.

DETAILED DESCRIPTION

This document discloses a powder formulation suitable for reconstitutionwith a pharmaceutically acceptable carrier to form a suspension oraldosage form of tadalafil. Advantages of the powder formulation anddosage form include prolonged stability, dose titration accuracy andbetter compliance in comparison with conventional immediate releasenon-suspension dosage forms.

Tadalafil is known as pyrazino [1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. Tadalafil is insolublein water. When crushed tadalafil tablets are simply added directly intowater or other soft food, the compound tends to settle rapidly andcannot be easily redistributed and as such would potentially affect thedose accuracy delivered to a patient.

The powder formulation and suspension dosage form disclosed hereineffectively resolved the above issues. After reconstitution, the uniformliquid suspension enables easy and accurate dose titration with animproved taste. The powder formulation and suspension dosage formdescribed in this patent document are applicable to Tadalafil as well assalts, isomers, complexes, polymorphs, hydrates, esters and prodrugsthereof.

While the following text may reference or exemplify specific embodimentsof a dosage form or a method of manufacturing the dosage from, it is notintended to limit the scope of the dosage form to such particularreference or examples. Various modifications may be made by thoseskilled in the art, in view of practical and economic considerations,such as the amount of individual excipients and the manufacturingcondition.

The articles “a” and “an” as used herein refers to “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement or component of an embodiment by the indefinite article “a” or“an” does not exclude the possibility that more than one element orcomponent is present.

The term “about” as used herein refers to the referenced numericindication plus or minus 10% of that referenced numeric indication.

The term “active ingredient” or “active pharmaceutical ingredient” (API)refers to a compound (e.g. tadalafil) that can be used for treating adisorder or condition in a subject (e.g., a patient), or for preventingone or more symptoms of such disorder or condition in the subject.

The term “bioequivalence” or “bioequivalent” refers to two formulations,dosage forms, products, or compositions of an active ingredient havingbiological equivalence. It is generally considered bioequivalent if the90% Confidence Interval (“CI”) of the relative mean Cmax, AUC(0-t) andAUC(0-∞) of the test formulation to reference formulation (i.e., brandproduct) is within 80.0% to 125.0% in the fasting state of a testedsubject.

The term “patient compliance” refers to the degree to which patientcorrectly follows medical advice.

The term “excipient” refers to any inert substance that may havespecific functions to the active ingredient (e.g., swelling agent,controlling-release, osmotic agent). An excipient provides withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability, etc., to the formulation of an activeingredient. A “suspending agent” is a type of excipient. An excipientmay function for multiple purposes.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissues,organs, and/or bodily fluids of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problems orcomplications commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable salts” means salts of tadalafilwhich are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Non-limiting examples ofsuch salts include acid addition salts formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, andphosphoric acid; or with organic acids such as 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid,3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy- 2-ene-1-carboxylicacid), 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, and trimethylacetic acid. It should berecognized that the particular anion or cation forming a part of anysalt of this invention is not critical, so long as the salt, as a whole,is pharmacologically acceptable. Additional examples of pharmaceuticallyacceptable salts and their methods of preparation and use are presentedin Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl &C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

The term “powder” as used herein refers to any composition orformulation which is dry and flowable. Non-limiting examples includegranules, flakes, spheroids and other forms which can be readilyprepared and mixed with an ingestible liquid to provide a desirableliquid suspension.

The term “wet granulation” refers to a process of using a liquid binderto lightly agglomerate the powder mixture.

The term “release”, “released”, “releasing”, and the like, when used inconnection with a pharmaceutical compression or dosage form, refers tothe process or the portion of the active ingredient that leaves thedosage form following contact with an aqueous environment. Unlessotherwise indicated, the quantity of an active ingredient released froma dosage form is measured by dissolution testing in water as describedin this invention. The results of the dissolution testing are reportedas % (w/w) released as a function of time or as the release time. Insome embodiments, complete release of an active ingredient occurs whenat least 90% of the active ingredient has been released from the dosageform.

The term “immediate-release” refers to those which disintegrate rapidlyand/or get dissolved to release the medicaments or active ingredient.For example, more than or equal to about 85% or more than or equal toabout 90% of an active pharmaceutical ingredient in an immediate releasedosage form is released in less than or equal to about 1 hour. In someembodiments, more than or equal to about 80% or more than or equal toabout 90% or more than or equal to about 95% of an active pharmaceuticalingredient in an immediate release dosage form is released in less thanor equal to about 30 minutes.

The term “Cmax” or “peak plasma exposure”, expressed in ng/mL, refers tothe point of maximum concentration of drug in plasma.

The term “area under curve (AUC)” or “total plasma exposure”, expressedin μg•hr/mL, refers to the total integrated area under plasma level timeprofile and expresses the total amount of the active ingredient thatcomes into systemic circulation after administration.

The term “D90” refers to the particle size corresponding to 90% of thecumulative undersize distribution by volume.

The term “pharmaceutically acceptable excipient or carrier” refers to anagent or a substance that enable an active ingredient or a compositionthereof to be formulated as tablets, pills, dragees, capsules, liquids,gels, syrups, slurries, suspensions and the like, for administration toa subject in need.

The term “sedimentation volume ratio” or “sedimentation ratio” refers toa ratio of the ultimate volume of sediment (Vu) to the original volumeof sediment (VO) before settling.

The term “subject” refers to a mammal, such as an animal or a human.Hence, the methods disclosed herein can be useful in human therapy andveterinary applications. In one embodiment, the subject is an animal. Inanother embodiment, the subject is a human.

The term “treat” or “treating” refers to attain or attaining abeneficial or desired result, such as a clinical result. In someembodiments, the beneficial or desired result is any one or more of thefollowing: inhibiting or suppressing the onset or development of acondition, reducing the severity of the condition, reducing the numberor severity of symptoms associated with the condition, increasing thequality of life of a patient suffering from the condition, decreasingthe dose of another medication required to treat the condition,enhancing the effect of another medication a patient is taking for thecondition, and prolonging the survival of a patient having thecondition.

An aspect of the document provides a powder formulation suitable forreconstitution with a pharmaceutically acceptable carrier to form astable suspension oral dosage form of tadalafil. The formulationincludes:

-   -   tadalafil, a pharmaceutically acceptable salt, an isomers, a        complex, a polymorphs, a hydrate, or an ester thereof;    -   a suspending agent in an amount ranging from about 0.1% to about        10% w/w based on the total weight of the formulation.

In some embodiments, the suspending agent, other excipients, and theirrespective amounts are selected so that they are effective formaintaining a sedimentation volume ratio of more than about 0.7, morethan about 0.8, more than about 0.9, or more than about 0.95 for aperiod of at least 12 hours, at least 24 hours, at least 48 hours, atleast 3 days, at least 5 days, at least 7 days, or at least 2 weeksafter the powder formulation is reconstituted into a suspension.

In some embodiments, the pharmaceutically acceptable carrier is water oran aqueous solution containing one or more agents or excipients. Thesalt of tadalafil includes for example HCl salt, salicylate salt,citrate salt and mandelate salt.

The amount of the suspending agent in the formulation can vary dependingon factors such as the dosage of tadalafil and the specific suspendingagent.

In some embodiments, the suspending agent is in an amount ranging fromabout 1% to about 8%, from about 1.5% to about 6%, from about 2% toabout 5%, or from about 2.5% to about 4%, w/w in the powder formulation.Non-limiting examples include about 1%, about 1.2%, about 1.4%, about1.8%, about 2%, about 2.2%, about 2.4%, about 2.5%, about 2.6%, about2.8%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%,about 6%, about 7%, or about 8%. In some embodiments, the suspendingagent is xanthan gum.

In some embodiments, the suspending agent is in an amount of from 0.5mg/ml to 10 mg/ml, from 0.5 mg/ml to 8 mg/ml, from 0.5 mg/ml to 6 mg/ml,after the powder formulation is reconstituted into the suspension. Inexemplary embodiments, the amount is about 2, about 3, about 4, about 5,or about 6 mg/ml after the powder formulation is reconstituted into thesuspension.

The suspending agent stabilizes the resulting suspension for an extendedperiod of time after the formulation is reconstituted with for examplewater or an aqueous solution. Various mechanical means, such as shaking,swirling, heating, or any combination thereof can be used to promote auniform suspension.

The suspending agent contributes to the stability of the suspensionafter reconstitution. In some embodiments, the suspending agent and itsamount are selected so that the suspension maintains a sedimentationratio of more than 0.8, more than 0.9, more than 0.95, or more than 0.98for a period of at least 10 minutes, at least 20 minutes, at least 20minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8hours, at least 12 hours, at least 24 hours, or at least 48 hours. Insome embodiments, the suspending agent, the one or more pharmaceuticallyacceptable excipients, and their respective amounts are selected so thatless than about 5%, less than about 3%, less than about 1%, less thanabout 0.5%, less than about 0.2%, or less than about 0.1% of thetadalafil or a pharmaceutically acceptable salt thereof is decomposedfor a period of at least 6 months, at least 5 months, at least 4 months,at least 3 months, at least 2 months, at least 1 month, at least 3weeks, at least 2 weeks or at least 1 week after the formulation isreconstituted into a suspension.

The ratio between tadalafil (or a pharmaceutically acceptable saltthereof) and the suspending agent ranges from about 40:1 to about 1:10by weight. In some embodiments, the ratio ranges from about 30:1 toabout 1:5, from about 20:1 to about 2:5, from about 10:1 to about 1:1 orfrom about 5:2 to about 5:6. Non-limiting examples of the ratio betweentadalafil (or a pharmaceutically acceptable salt thereof) and thesuspending agent include about 10:2, about 10:3, about 10:4, about 10:5,about 10:6, about 10:7, about 10:8, about 10:9, about 10:10, about10:11, about 10:12, about 10:13, about 10:14, and about 10:15.

Non-limiting examples of the suspending agent include hydrocolloid gumssuch as xanthan gum, guar gum, locustbean gum, gum tragacanth, veegum,sodium alginate, carrageenan; cellulosic derivatives such as sodiumcarboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose,hydroxypropyl methylcellulose; polysaccharides such as starch andpregelatinised starch; alginates such as sodium alginate; acrylic acidcopolymers such as carbopols; Polyvinylpyrrolidone; aluminiummagnesiumsilicate; and combinations thereof. In some embodiments, the suspendingagent is hydrocolloid gum. In some embodiments, the suspending agent isxanthan gum.

The powder formulation after reconstitution into a suspension providesan in vitro release as measured by USP dissolution apparatus 2. In someembodiments, at least about 95%, at least about 90%, at least about 85%,at least about 80%, at least about 75%, at least about 65% or at leastabout 50% of the tadalafil is released in a medium of 0.5% sodium laurylsulphate (SLS) after 10 minutes (USP dissolution apparatus 2, in 1000 mlof 0.5% SLS at 50 rpm).

The power formulation can also provide a release of tadalafilbioequivalent to non-suspension formulation of tadalafil at the samedose. Examples of non-suspension formulation of tadalafil includetadalafil tablets. In some embodiments, the dose of tadalafil in theformulation ranges from about 2 mg to about 50 mg, including for exampleabout 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg andabout 80 mg.

The tadalafil or the pharmaceutically acceptable salt thereof or thederivative thereof used for the preparation of the powder formulationhas a D90 of less than about 80 μm, less than about 70 μm, less thanabout 60 μm, less than about 50 μm, less than about 40 μm, less thanabout 30 μm, less than about 20 μm, less than about 10 μm. In someembodiments, the D90 ranges from about 3 μm to about 40 μm, from about 2μm to about 30 μm, from about 1 μm to about 20 μm, or from about 0.5 μmto about 10 μm.

The formulation can contain one or more additional carrier or excipientincluding for example, surface active agents, sweeteners, lubricants,glidants, diluents, smoothing agents, suspension agents, film formingsubstances, buffering agents and coating assistants, or a combinationthereof. In some embodiments, the formulation further contains a diluentincluding for example sucrose, dextrose, mannitol, sorbitol, maltitol,starch, lactose, microcrystalline cellulose, and any combination thereofin about 10% to about 98% by weight of the powder formulation.

In some embodiments, the formulation further contains a diluent (e.g.sorbitol) ranging from about 50% to about 85% or from about 70% to about80% by weight in the powder formulation. Non-limiting examples of theamount of the diluent (e.g. sorbitol) in the formulation include about55%, about 60%, about 65%, about 68%, about 70%, about 72%, about 75%,about 78%, about 80%, about 82%, about 84%, and 86%.

In some embodiments, the formulation further contains glidants includingfor example silicon dioxide, starch, talc and any combination thereofranging from about 0.1% to about 10%, from about 1% to about 6%,preferably from about 2% to about 5% from about 1% to about 3.5%, orfrom about 2% to about 2.5%. Exemplary amounts of glidant include 0.5%,0.8%, 1%, 1.5%, 1.8%, 2%, 2.5%, 3%, 3.5%, and 4% by weight in theformulation. In some embodiments, the glidant is silicon dioxide.

In some embodiments, the formulation further contains a preservativeselected from the group consisting of Methyl Paraben or its sodium salt,Ethyl Paraben or its sodium salt, Propyl Paraben or its sodium salt,Sodium Benzoate, benzoic acid, Sorbic Acid, potassium sorbate, propionicacid and any combination thereof in about 0% to about 10%.

In some embodiments, the formulation further contains a buffering agentincluding for example sodium citrate, citric acid, fumaric acid,tartaric acid, potassium citrate, sodium bicarbonate, potassiumbicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate,sodium hydroxide and potassium dihydrogen phosphate. The bufferconcentration after reconstitution of the powder formulation into asuspension ranges from about 10 mM to about 200 mM, from about 10 mM toabout 100 mM, or from about 10 mM to about 50 mM. In some embodiments,the pH of the suspension ranges from about 1 to about 7, from about 2 toabout 6 or from about 2.8 to about 4.8.

In some embodiments, the reconstituted suspension is easily pourable andhas a viscosity in the range of 10 to 5000 cP at 25° C. In someembodiments, the viscosity is in the range from about 20 to 4000 cP at25° C., from about 30 to 3000 cP at 25° C., from about 40 to 2000 cP at25° C. Non-limiting examples of viscosity including 60, 80, 100, 150,200, 400, 400, 500, 600, 700, 800, 1000, 1200, 1400, 1600, and 1800 cp.

In some embodiments, the formulation further contains a sweetener.Non-limiting examples include sucrose, glucose, sorbitol, sucralose,aspartame, saccharin sodium and any other pharmaceutically acceptablesweetener or combination thereof. The amount of the sweetener used inthe powder for oral suspension compositions is typically in the range offrom about 0.5% to about 10% w/w based on the total weight of the powderformulation.

In some embodiments, the formulation further contains a flavor.Non-limiting examples include grenadine flavor, berry flavor, strawberryflavor, banana flavor, orange flavor and peppermint flavor. The amountof the flavor in the powder for oral suspension is between about 0.1% toabout 5% w/w based on the total weight of the powder formulation.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the suspension prepared from the powder formulationprovides a release of the tadalafil bioequivalent to the same dose oftadalafil in immediate release tablet form. In some embodiments, thesuspending agent, the one or more pharmaceutically acceptableexcipients, and their respective amounts are selected so that the ratioof area under curve (AUC 0-inf) between tadalafil suspension totadalafil in immediate release tablet form with the same dose rangesfrom about 0.8 to about 1.25, preferably from about 0.9 to about 1.1,after oral administration. Non-limiting examples of the ratio includeabout 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.3, andabout 1.5.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the ratio of a maximum tadalafil plasma concentration(Cmax) between tadalafil suspension to tadalafil in immediate releasetablet form with the same dose ranges from about 0.7 to about 1.20,preferably from about 0.75 to about 0.90, after oral administration.Non-limiting examples of the ratio include about 0.8, about 0.85, about0.9, about 0.95, about 1, about 1.05, about 1.1, and about 1.5.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the plasma concentration profile at steady state ischaracterized by a maximum tadalafil plasma concentration to averageplasma concentration ratio (Cmax/Cave) ranging from about 1.4 to about1.9, preferably from about 1.45 to about 1.65, after administration.Non-limiting examples of the ratio include about 1.5, about 1.55, about1.6, about 1.7 and about 1.8.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the plasma concentration profile at steady state ischaracterized by a minimum tadalafil plasma concentration to averageplasma concentration ratio (Cmin/Cave) ranging from about 0.5 to about0.8, preferably from about 0.6 to about 0.7, after administration.Non-limiting examples of the ratio include about 0.55, about 0.6, about0.65, about 0.7, and about 0.8.

Another aspect of this patent document discloses a suspension including(a) tadalafil or a pharmaceutically acceptable salt thereof or aderivative thereof; and (b) a suspending agent, wherein the suspendingagent is effective to keep the stable suspension after the suspension isprepared.

The ratio between the tadalafil (or a pharmaceutically acceptable saltthereof or a derivative thereof) and the suspending agent in thesuspension is the same as in the above described formulation. In someembodiments, the ratio ranges from about 40:1 to abut 1:10 or from about20:1 to about 1:2 by weight. In some embodiments, the ratio is about 5:4by weight.

In some embodiments, the ratio ranges from about 30:1 to about 1:5, fromabout 20:1 to about 2:5, from about 10:1 to about 1:1 or from about 5:2to about 5:6. Non-limiting examples of the ratio between tadalafil (or apharmaceutically acceptable salt thereof) and the suspending agentinclude about 10:2, about 10:3, about 10:4, about 10:5, about 10:6,about 10:7, about 10:8, about 10:9, about 10:10, about 10:11, about10:12, about 10:13, about 10:14, and about 10:15.

The particle size of the tadalafil, the suspending agent and otherexcipients (e.g. diluent, buffering agent) are also as described above.In some embodiments, the suspending agent is hydrocolloid gum. In someembodiments, the suspending agent is xanthan gum. Other excipients orcarriers can be added to the suspension in any suitable sequence.

The concentration of the tadalafil (or a pharmaceutically acceptablesalt thereof or a derivative thereof) in the suspension is in the rangeof from about 1 to about 50 mg/ml, from about 1 to about 20 mg/ml, orfrom about 1 to 15 mg/ml. In some embodiments, the concentration is 2,3, 4, 5, 6, 8, 10, 15 or 20 mg/ml.

The concentration of the suspending agent in the suspension is in therange of from about 0.1 mg/ml to about 20 mg/ml, from about 0.2 mg/ml toabout 10 mg/ml, from about 0.5 mg/ml to about 8 mg/ml, from about 1mg/ml to about 6 mg/ml. Non-limiting examples of the concentration ofthe suspending agent in the suspension include 1, 2, 3, 4, 5, 6, 7, 8and 9 mg/ml. Examples of the suspending agent are as described above. Insome embodiments, the suspending agent is xanthan gum.

In some embodiments, the suspending agent is in an amount of from 0.5mg/ml to 10 mg/ml, from 0.5 mg/ml to 8 mg/ml, from 0.5 mg/ml to 6 mg/ml,from 2.5 mg/ml to 6 mg/ml, from 3 mg/ml to 5 mg/ml, or from 3 mg/ml to 4mg/ml in the suspension. In exemplary embodiments, the suspending agentis in an amount of about 2, about 2.5, about 3, about 3.5, about 4,about 4.5, about 5, or about 6 mg/ml in the suspension.

In some embodiments, the suspending agent and its amount are selected sothat the suspension maintains a sedimentation ratio of more than 0.8,more than 0.9, more than 0.95, or more than 0.98 for a period of atleast 10 minutes, at least 20 minutes, at least 20 minutes, at least 1hour, at least 2 hours, at least 4 hour, at least 8 hours, at least 12hours, at least 24 hours, or at least 48 hours. In some embodiments, thesuspending agent, the one or more pharmaceutically acceptableexcipients, and their respective amounts are selected so that less thanabout 5%, less than about 3%, less than about 1%, less than about 0.5%,less than about 0.2%, or less than about 0.1% of the tadalafil or apharmaceutically acceptable salt thereof is decomposed for a period ofat least 6 months, at least 5 months, at least 4 months, at least 3months, at least 2 months, at least 1 month, at least 3 weeks, or atleast 2 weeks.

In some embodiments, at least about 95%, at least about 90%, at leastabout 85%, at least about 80%, at least about 75%, at least about 65% orat least about 50% of the tadalafil is released in a medium of 0.5%sodium lauryl sulphate (SLS) after 10 minutes (USP dissolution apparatus2, in 1000 ml of 0.5% SLS at 50 rpm).

The scope and examples of various excipients and their amounts are asdescribed above. In some embodiments, the suspending agent, the one ormore pharmaceutically acceptable excipients, and their respectiveamounts are selected so that the suspension provides a release of thetadalafil bioequivalent to the same dose of tadalafil in immediaterelease tablet form. In some embodiments, the suspending agent, the oneor more pharmaceutically acceptable excipients, and their respectiveamounts are selected so that the ratio of area under curve (AUC 0-inf)between tadalafil suspension to tadalafil in immediate release tabletform with the same dose ranges from about 0.8 to about 1.25, preferablyfrom about 0.9 to about 1.1, after oral administration. Non-limitingexamples of the ratio include about 0.85, about 0.9, about 0.95, about1, and about 1.5.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the ratio of a maximum tadalafil plasma concentration(Cmax) between tadalafil suspension to tadalafil in immediate releasetablet form with the same dose ranges from about 0.7 to about 1.20,preferably from about 0.75 to about 0.90, after oral administration.Non-limiting examples of the ratio include about 0.8, about 0.85, about0.9, about 0.95, about 1, about 1.05, about 1.1, and about 1.5.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the plasma concentration profile at steady state ischaracterized by a maximum tadalafil plasma concentration to averageplasma concentration ratio (Cmax/Cave) ranging from about 1.4 to about1.9, preferably from about 1.45 to about 1.65, after administration.Non-limiting examples of the ratio include about 1.5, about 1.52, about1.55, about 1.56, about 1.58, about 1.6, about 1.62, about 1.65, about1.7, about 1.75, and about 1.8.

In some embodiments, the suspending agent, the one or morepharmaceutically acceptable excipients, and their respective amounts areselected so that the plasma concentration profile at steady state ischaracterized by a minimum tadalafil plasma concentration to averageplasma concentration ratio (Cmin/Cave) ranging from about 0.5 to about0.8, preferably from about 0.6 to about 0.7, after administration.Non-limiting examples of the ratio include about 0.55, about 0.6, about0.62, about 0.65, about 0.66, about 0.68, about 0.7, and about 0.8.

The suspension can be prepared from the above described powderformulation by reconstitution or by mixing the necessary components insuitable means as long as the resulting suspension achieves a desirableprofile for oral administration. For example, the suspension can beprepared by adding a pre-calculated amount of water to the abovedescribed powder formulation containing suitable dosage of tadalafil orits salt and thoroughly mix the combined substances. By using ameasuring cup or a syringe, a precise dosage can be obtained for oraladministration. In exemplary embodiments, the powder formulation can besupplied in vials or bottles for multiple use or in unit dosage sachetsfor single use. In some embodiments, the powder formulation afterreconstitution with water provides a liquid suspension containing 50 mgof tadalafil per 10 ml of liquid suspension.

The excellent stability of the powder formulation and the suspensionallows for accurate dose titration and easy administration. This isespecially important for pediatric patients and patients with dysphagiawho cannot swallow tablets due to its size.

Another aspect of the patent document provides a method of preparing theabove described formulation. The method generally includes mixing thetadalafil (or a pharmaceutically acceptable salt thereof or a derivativethereof), the suspending agent and other excipients. The ratio betweenthe tadalafil (or a pharmaceutically acceptable salt thereof or aderivative thereof) and the suspending agent in the suspension is thesame as in the above described formulation. The amounts of otherexcipients are as described above. Additional carriers or excipientsdescribed above can also be added in the mixture. Exemplary methods ofpreparation include dry powder blending, wet granulation, drygranulation by compaction/slugging, spray drying, hot melt extrusion,extrusion spheronization and fluidized bed granulation. As describedabove, in order to have good uniformity, the active ingredient and allthe excipients in the powder formulation should have suitable particlesize range and need to pass certain mesh before using, such as mesh 20,40, 60, 80 or 100.

In exemplary embodiments, the method includes the following steps:

-   -   (a) mixing tadalafil or a pharmaceutically acceptable salt        thereof with a first portion of glidant to obtain a first        mixture; and    -   (b) mixing the first mixture with one or more additional        excipients.

In some embodiments, the method further includes mixing the firstmixture with a first portion of diluent prior to step (b). Preferably,the glidant, diluant and/or other ingredients/excipients is passedthrough mesh of suitable size. In some embodiments, the one or moreadditional excipients include a second portion of glidant and/or asecond portion of diluent. In some embodiments, the method furtherincludes mixing the first mixture, during step (b) or after step (b)with a second portion of the glidant and/or a second portion of diluent.In some embodiments, the glidant is silicon dioxide. In someembodiments, the diluent is sorbitol. In some embodiments, the ratiobetween the first portion of glidant and the second portion of glidantranges from about 1:2 to about 1:5, from about 1:2 to about 1:4, or fromabout 1:3 to about 1:4. In some embodiments, the ratio between the firstportion of diluent and the second portion of diluent ranges from about1:1 to about 1:2, including for example from about 1:1.2, about 1:1.4,about 1:1.6 or about 1:1.8.

Another aspect of the patent document provides a method of treating adisease or condition using the powder formulation or the suspensiondescribed above. The powder formulation needs to be reconstituted into asuspension. The suspension contains for example, 5 mg/ml of tadalafil(or a pharmaceutically acceptable salt thereof or a derivative thereof)for oral administration to a subject in need. Examples of the disease orcondition include erectile dysfunction, Benign Prostatic Hyperplasia andpulmonary arterial hypertension. Other exemplary applications includetreatment of Heart failure, hypertension, Left ventricle diastolicdysfunction, scleroderma spectrum of disease, Systemic Sclerosis,Raynaud's, fetal growth restriction, Mountain Sickness, Skeletal Muscleand Perceptual Fatigue, Interstitial Lung Disease of Scleroderma,Chronic Obstructive Pulmonary Disease, Duchenne Muscular Dystrophy.

EXAMPLES Example 1

Formulation compositions of tadalafil powder for oral suspension,formulation 1-5, were prepared and are shown in table 1. The dissolutionof these formulation is shown in FIGS. 1 and 2.

TABLE 1 Formulation compositions of tadalafil powder for oral suspensionFormulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation 5 %w/w % w/w % w/w % w/w % w/w Description (powder) (powder) (powder)(powder) (powder) Tadalafil 4.28 4.28 4.28 3.20 2.14 Sucralose 2.14 2.142.14 1.60 1.07 Xanthan 2.57 3.43 4.28 2.56 1.71 gum Colloidal 2.5 2.52.5 1.87 1.25 silicon dioxide Sorbitol 78.16 77.3 76.45 83.06 88.65Citric acid 6 6 6 4.48 3 anhydrous Sodium 3.5 3.5 3.5 2.61 1.75 citratedihydrate Sodium 0.86 0.86 0.86 0.64 0.43 benzoate Total 100 100 100 100100

The viscosity of suspension after reconstitution of formulation 1, 2 and3 are 144, 698.7 and 749 cp respectively. Formulation 1 has the lowviscosity, where formulation 3 has the high viscosity and slowerdissolution rate (FIG. 1).

TABLE 2 The effect of sorbitol percentage on powder BU, suspensionviscosity and dissolution Formulation 2 Formulation 4 Formulation 5Sorbitol percentage 77.3% 82.86% 88.86% Blend uniformity 4.8 12.6 21.1(BU), AV value Viscosity 688 cp 701.3 cp 760 cp Dissolution at 10 min92.13% 81.59% 59.33%

The effect of sorbitol percentage is shown in table 2. Higher sorbitolpercentage in the formulation results in worse blend uniformity (higherAV value), higher viscosity and lower dissolution rate (FIG. 2).

TABLE 3 Formulation compositions of tadalafil powder for oral suspensionwith different percentage of silicon dioxide Formulation 6 Formulation 7Formulation 8 Formulation 9 Formulation 10 % w/w % w/w % w/w % w/w % w/wDescription (powder) (powder) (powder) (powder) (powder) Tadalafil 4.284.28 4.17 4.14 4.09 Sucralose 2.14 2.14 1.04 1.03 1.02 Xanthan 3.43 3.431.67 1.65 1.63 gum Colloidal 1.5 0.57 0.49 1.21 2.35 silicon dioxideSorbitol 78.3 79.23 87.61 86.97 85.96 Citric acid 6 6 2.92 2.89 2.86anhydrous Sodium 3.5 3.5 1.70 1.69 1.67 citrate dihydrate Sodium 0.860.86 0.42 0.41 0.41 benzoate Total solids 100 100 100 100 100 Blend 12.828.4 14.54 6.44 4.78 uniformity, AV valueFormulation compositions of tadalafil powder for oral suspension withdifferent percentage of silicon dioxide is shown in table 3. The datacomparing within group 1 (Formulation 2, 6 and 7) or within group 2(Formulation 8, 9 and 10) shows that higher silicon dioxide percentagein the formulation results in better blend uniformity (lower AV value).However, too much silicon dioxide (>3%) in the formulation will make theprocess difficult.

The preparation step of tadalafil powder for oral suspension was asfollowing:

-   -   1. API was mixed with Colloidal silicon dioxide (SiO₂) (part 1)        for 10 min (20 rpm)    -   2. Sorbitol (part 1) also pass through the Comil for de-lumping    -   3. The API- SiO2 mixture and Sorbitol 1 were mixed in the        blender for 5 min (20 rpm) and then pass through the Comil    -   4. All other milled excipients (including SiO₂ part 2 and        Sorbitol part 2) were added and mixed in the blend for 10 min        (20 rpm) to form the final blend.

API need to be mixed with partial Colloidal silicon dioxide (SiO2)first, without this step, the final formulation has the low assay(89.9%) and poor blend uniformity.

Various techniques can be employed in the preparation, including forexample, dry powder blending, wet granulation, dry granulation bycompaction or slugging, spray drying, hot melt extrusion, extrusionspheronization and fluidized bed granulation.

Tadalafil powder for oral suspension was reconstituted to form 5 mg/mlsuspension. The assay of suspension in the up, middle and bottomposition are 99.8%, 99.0% and 99.7% respectively, which indicate thatthe homogeneity of suspension was acceptable. The viscosity ofsuspension was ˜688 cp.

The reconstituted tadalafil suspension was stirred to evaluate thephysical and chemical stability. The crystalline form of tadalafil wasunchanged after 6 months (FIG. 3), and no additional impurity wasobserved, indicating that reconstituted suspension has the good physicaland chemical stability.

Tadalafil oral suspension were also prepared and formulationcompositions are shown in table 4. The suspension is physically andchemically stable and has an in vitro release of at least about 75% ofthe tadalafil within about 10 minutes under USP dissolution apparatus 2in 1000 ml of 0.5% SLS at 50 rpm.

TABLE 4 Formulation compositions of tadalafil oral suspensionFormulation 11 Formulation 12 Description (suspension) mg/ml(suspension) mg/ml Tadalafil 5 10 Sucralose 2.5 2.5 Xanthan gum 4 4Colloidal silicon 2.92 2.92 dioxide Sorbitol 90.25 210.33 Citric acidanhydrous 7 7 Sodium citrate 4.08 4.08 dihydrate Sodium benzoate 1 1Viscosity (cp) 688 cp 733 cp

It will be appreciated by persons skilled in the art that fibersdescribed herein are not limited to what has been particularly shown anddescribed. Rather, the scope of the formulation, the suspension and themethod are defined by the claims which follow. It should further beunderstood that the above description is only representative ofillustrative examples of embodiments. The description has not attemptedto exhaustively enumerate all possible variations. The alternateembodiments may not have been presented for a specific component of theformulation or step of the method, and may result from a differentcombination of described components/excipients or steps, or that otherun-described alternate embodiments may be available for acomponent/excipient or a step, is not to be considered a disclaimer ofthose alternate embodiments. It will be appreciated that many of thoseun-described embodiments are within the literal scope of the followingclaims, and others are equivalent.

1-43. (canceled)
 44. A method of achieving in a subject a selected areaunder curve (AUC 0-inf) from a tadalafil suspension, comprisingreconstituting a powder formulation into the suspension andadministering to the subject the suspension, wherein the ratio betweenthe AUC from the suspension and the AUC from an in immediate releasetadalafil tablet form with the same dose ranges from about 0.8 to about1.25, wherein the ratio between maximum tadalafil plasma concentration(C_(max)) to average plasma concentration (C_(ave)) ranging from about1.4 to about 1.9, wherein the powder formulation comprises: tadalafil ora pharmaceutically acceptable salt thereof; a suspending agent, whereinthe suspending agent is in an amount ranging from about 0.1% to about10% w/w in the powder formulation; and one or more pharmaceuticallyacceptable excipients.
 45. The method formulation of claim 44, whereinthe suspending agent, the one or more pharmaceutically acceptableexcipients, and their respective amounts are selected so that thesuspension provides an in vitro release of at least 75% of the tadalafilwithin about 10 minutes under USP dissolution apparatus 2 in 1000 ml of0.5% SLS at 50 rpm.
 46. The method formulation of claim 44, wherein thesuspending agent, the one or more pharmaceutically acceptableexcipients, and their respective amounts are selected so that the ratiobetween the AUC from the suspension and the AUC from the in immediaterelease tadalafil tablet form with the same dose ranges from about 0.9to about 1.1.
 47. The method formulation of claim 44, wherein thesuspending agent, the one or more pharmaceutically acceptableexcipients, and their respective amounts are selected so that the ratiobetween the C_(max) of the tadalafil suspension and a Cmax of theimmediate release tablet form ranges from about 0.7 to about 1.20. 48.The method formulation of claim 44, wherein the suspending agent, theone or more pharmaceutically acceptable excipients, and their respectiveamounts are selected so that the ratio between a maximum tadalafilplasma concentration (C_(max)) of the tadalafil suspension and a C_(max)of the immediate release tablet form ranges from about 0.9 to about 1.1.49. The method formulation of claim 44, wherein the suspending agent,the one or more pharmaceutically acceptable excipients, and theirrespective amounts are selected so that the ratio between C_(max) toaverage plasma concentration (C_(ave)) ranging from about 1.45 to about1.65.
 50. The method formulation of claim 44, wherein the suspendingagent, the one or more pharmaceutically acceptable excipients, and theirrespective amounts are selected so that the ratio between minimumtadalafil plasma concentration (C_(min)) to C_(ave) ranging from about0.6 to about 0.8.
 51. The method of claim 44, wherein the powderformulation further comprises a glidant ranging from about 1% to about3.5% by weight of the powder formulation.
 52. The method formulation ofclaim 51, where the glidant is silicon dioxide.
 53. The methodformulation of claim 44, further comprising a diluent selected from thegroup consisting of sucrose, dextrose, mannitol, sorbitol, maltitol,starch, lactose, microcrystalline cellulose, and any combinationthereof, wherein the diluent ranges from about 10% to about 98% byweight of the powder formulation.
 54. The method formulation of claim44, which further comprises sorbitol ranging from about 50% to about 85%by weight in the powder formulation.
 55. The method formulation of claim44, which further comprises sorbitol ranging from about 70% to about85%.
 56. The method of claim 44, wherein the suspending agent is in anamount ranging from about 1% to about 5% w/w in the powder formulation.57. The method formulation of claim 44, wherein the tadalafil or thepharmaceutically acceptable salt thereof and the suspending agent have aratio ranging from about 10:1 to about 5:8 by weight.
 58. The methodformulation of claim 44, wherein the tadalafil or the pharmaceuticallyacceptable salt thereof and the suspending agent have a ratio of about5:4 by weight.
 59. The method formulation of claim 44, wherein thesuspending agent is selected from the group consisting of hydrocolloidgum, cellulosic derivative, a polysaccharide, alginate, acrylic acidcopolymer, Polyvinylpyrrolidone, aluminiummagnesium silicate, and anycombination thereof.
 60. The method formulation of claim 44, wherein thesuspending agent is hydrocolloid gum.
 61. The method formulation ofclaim 44, wherein the suspending agent and its amount are selected sothat the reconstituted suspension maintains a sedimentation ratio ofmore than 0.9 in a sitting, non-stirred condition for at least 24 hours.62. The method formulation of claim 44, wherein the suspending agent,the one or more pharmaceutically acceptable excipients, and theirrespective amounts are selected so that the suspension prepared from thepowder formulation provides a release of the tadalafil bioequivalent tothe same dose of tadalafil in immediate release tablet form.
 63. Themethod formulation of claim 44, wherein the subject has been diagnosedwith erectile dysfunction, enlarged prostate, pulmonary arterialhypertension, heart failure, hypertension, left ventricle diastolicdysfunction, scleroderma spectrum of disease, systemic sclerosis, fetalgrowth restriction, skeletal muscle and perceptual fatigue, interstitiallung disease of scleroderma, chronic obstructive pulmonary disease,duchenne muscular dystrophy.